Cancer is a disease that is the second leading cause of death next to heart attacks in the United States. There has been tremendous research in the development of new compounds and therapies in the treatment of this devastating disease.
Boron neutron-capture therapy (BNCT) is a mode of therapy used in the treatment of cancer. BNCT involves utilizing a boron containing compound that is selectively accumulated in the tumor cell. Once accumulated in the tumor cell, the boron containing compound is irradiated with thermalized neutrons leading to capture of the neutrons and release of high linear-energy-transfer (LET) radiation particles consisting of alpha particles (.sup.4 He) and lithium ions (.sup.7 Li). These particles cause direct DNA damage and tumor cell death.
In the clinical setting, BNCT has been used in the treatment of mammals with malignant brain tumors. The treatment involves administering to the mammal a boron containing compound. Preferably, the boronated compound used should have a high intracellular concentration in the tumor, within the radiation volume. Following administration of the boronated compound, the mammal's head is then irradiated in the general area of the brain tumor with an incident beam or field of thermal (&lt;0.5 eV) or epithermal (0.5 eV-10 keV) neutrons. These neutrons become progressively thermalized (average energy.apprxeq.0.04 eV) as they penetrate deeper into the head. The boron containing nuclei in and around the brain tumor undergo a nuclear reaction immediately after capturing a neutron. This reaction produces high LET radiation particles consisting of alpha particles (.sup.4 He) and lithium ions (.sup.7 Li). These particles travel a distance comparable to or slightly less than the diameter of a typical tumor cell and cause the destruction of the tumor cell. (See, Barth et al., 1992).
In order to minimize the destruction of normal (non-tumor) tissue, it is particularly important that there be robust uptake of boron in the tumor relative to normal tissues within the neutron-irradiated target volume. It has been postulated that tumor boron concentrations should be greater than 30 .mu.g B/g (Miura, et al., 1996).
Many classes of compounds have been synthesized for BNCT. For example, U.S. Pat. No. 5,599,796 to Schinazi et al. disclose boron-containing compounds that are sufficiently lipophilic to pass through membranes in a quantity high enough for BNCT. The boron containing compounds disclosed include Na.sub.2 B.sub.12 H.sub.11 SH (sodium borocaptate or BSH), carboranyl-containing nucleosides and oligonucleotides such as 5-carboranyl-2'-deoxyuridine and 5-o-carboranyl-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)uracil. Other nucleosides and oligonucleotides bearing an -O-[(carboran-1-yl)alkyl]phosphate, S-[(carboran-1-yl)-alkyl]-phosphorothioate, or Se-[(carboran-1-yl)alkyl]phosphoroselenoate in place of the (carboran-1-yl)-phosphonate moiety are disclosed as well.
Boron containing amino acid compounds have also been synthesized for BNCT. For example, U.S. Pat. No. 5,630,786 to Griffin et al. disclose borane anion derivatives that have two polyhedral borane anion cages linked together to form a structure comprising 20 boron atoms used in BNCT. These compounds may be constructed from boron-rich alpha-amino acids or boron enriched oligophosphates.
Efforts have been made to synthesize additional boron containing amino acid analogs and nucleosides used in BNCT. For example, U.S. Pat. No. 5,466,679 to Soloway et al. disclose novel carboranyl uridines including dodecaboran(12)-1-yl)hexyl-2'-deoxyuridine and novel boronated amino acids such as p-(o-carboran-1-yl)-phenylalanine and 5-[6-(1,2-dicarba-closo-dodecaboran(12)-1-ylpentylthio]-2'-deoxyuridine.
Similarly, U.S. Pat. No. 4,587,359 to Spielvogel et al. disclose boron containing nucleosides, nucleotides and amino acids used in BNCT. More particularly, the boron analogs disclosed are amine-carbamoylborane compounds of the formula R.sub.1 R.sub.2 NHBH.sub.2 C(O)NHR.sub.3 wherein R.sub.1 and R.sub.2 are hydrogen or certain alkyl moieties and R.sub.3 is an alkyl. These amine-carbamoylborane compounds are prepared by an amine displacement reaction using reactants that are difficult to obtain.
Some boron containing amino acid compounds have been used clinically in BNCT. One such amino acid is p-boronophenylalanine (BPA). This boron containing amino acid has been used at Brookhaven National laboratory Medical Department. BPA has been reported to be minimally toxic to normal tissues and organs. (See Coderre, et al., 1997).
Based on the foregoing, there is still a need for new boron containing amino acid compounds which are readily accumulated in tumor cells, methods of preparing these compounds and methods of using these new boron containing amino acid compounds in BNCT for treating tumors.